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Research Lab

Dr. Bear’s laboratory has a major interest in understanding the molecular basis for ion channel activity. She pursued postdoctoral training in patch clamp electrophysiology because of its power to provide insight into mechanisms underlying single ion channel activity. Her laboratory together with Dr. Jack Riordan, provided the first direct evidence that the CFTR protein functioned as a cyclic AMP regulated chloride channel. Since this discovery, the work in her laboratory led to key findings that underpin the current understanding in the field regarding the mechanism of action of this protein and the intrinsic defects induced by disease-causing mutations of the CFTR genes. Her laboratory has also contributed to the larger field of membrane protein assembly and function through the development of novel methods for membrane protein purification and functional reconstitution. These methods have also been successfully applied to discover the mechanisms underlying the correction of mutant CFTR protein by emerging small molecule therapeutics and in discovering new lead compounds targeting the major CF causing mutant protein. Currently, in collaboration with the stem cell community in Toronto, her laboratory has been successful in developing methodology suitable for measuring channel function in epithelia differentiated from iPS cells.

Research Description

Research in Cystic Fibrosis and Kidney Disease

Our research is focused on two areas:

Cystic Fibrosis Research

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF), the most common fatal congenital disease amongst caucasians. Our work has provided direct evidence that CFTR acts as a phosphorylation and ATP regulated chloride channel and we have characterized the functional properties of the major CF-causing mutations. Currently, we are developing chemical-biology approaches to define the molecular lesion caused by these disease-causing mutations and to identify the molecular targets for therapeutics.

As Co-Director (with Dr. F. Ratjen) of the SickKids Cystic Fibrosis Centre, Dr. Bear is coordinating efforts to discover small molecules and peptides that are effective in correcting the trafficking and functional defects exhibited by CF mutants. Promising “hits” generated through structure-based drug design or high-throughput screens are currently undergoing validation in human respiratory epithelial cultures and in in-vivo studies of transgenic mice, possessing the major CF mutation. Sensitive clinical assays of drug efficacy and safety are being developed and validated to enhance translation of novel therapies.

Kidney Disease Research

Mutations in ClC-5, a chloride/proton antiporter causes Dent’s disease – a disease which is associated with proteinuria and renal failure in severe cases. The goal of our research is to understand how ClC-5 contributes (in a complex of other transporters and signaling proteins) to effective protein reabsorption by the kidney. Further, we will define the molecular basis for the renal pathology associated with disease-causing mutations in ClC-5 and identify protein targets for therapeutic intervention.